The present invention relates to a pharmaceutical composition for the prevention or treatment of itching comprising a prostaglandin D2 (PGD2) receptor antagonist.
PGD2 is a major prostanoid released from mast cells in which it is produced through PGG2 and PGH2 from arachidonic acid by the action of cyclooxygenase activated by immunological or unimmunological stimulation. PGD2 has been known to cause allergic disorders such as allergic rhinitis and allergic conjunctivitis because it shows various physiological effects such as induction of nasal obstruction, vasodilator effect, wandering of eosinophils and the like. Accordingly, PGD2 receptor antagonists have been thought to be useful for the treatment thereof (WO97/00853).
Moreover, a large quantity of PGD2 is also released from macrophages, so PGD2 may play a role in causing an inflammatory response independent of allergy.
On the other hand, itching has been known to be accompanied by diseases such as atopic dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis and the like as well as inflammatory responses such as swelling and the like. Moreover, the action accompanied by itching, for example scratching, knocking and the like may worsen the condition of the above-mentioned diseases. Therefore, the development of a compound for the treatment of itching has been desired, which is further expected to be a pharmaceutical composition for the prevention or treatment of diseases secondarily caused by the action against itching, for example cararacta, retinal detachment, inflammation, infection, dysgryphia and the like.
At present, antihistaminic agents are used as therapeutic agents for itching. They show an effect on swelling, but the effect against itching is by no means sufficient. Thus, it is suggested in Allergology Int., 1997, 46, 117-124 that itching may be caused by a mediator other than histamine.
A PGD2 receptor antagonist used in the present invention has been known to be useful for the treatment of allergic condition caused by PGD2 such as rhinitis and the like (WO97/00853). Any positive data concerning the prevention or treatment of itching has not been described.
On the other hand, it is described in J. Pharmacol. Exp. Ther., 279, 137-142, 1996 that instillation of PGD2 in guinea pig induces itching, which is inhibited by a PGD2 receptor antagonist, BWA868C. But it is not described that a PGD2 receptor antagonist is useful for the treatment of itching caused by allergy. Further described is that a PGD2 receptor antagonist, BWA868C, can not inhibit itching caused by antigens at all, which is similar to disease models.
On the other hand, it is described that Ramatroban, inhibiting the contraction of smooth muscle of bronchus caused by TXA2 or PGD2 stimulation, is efficacious against contact dermatitis or atopic dermatitis mediated by delayed allergy (WO97/44031). However, Ramatroban described in said specification is a TXA2 receptor antagonist, but not a PGD2 receptor antagonist. Moreover, the therapeutic effect of Ramatroban against atopic dermatitis is based on the suppression of swelling caused by the delayed-type allergy reaction. Thus, the suppression effect against itching is not described. Therefore, it is not suggested that a PGD2 receptor antagonist of the present invention suppresses itching and useful for the treatment of atopic dermatitis.
PGD2, a mediator mass-produced through allergy reaction, is supposed to play an important role as a mediator in itching. Indeed, we have discovered through an experiment using mice that a PGD2 receptor antagonist is efficacious against itching to accomplish the present invention. Therefore, the present invention provides a composition for the prevention or treatment of itching comprising a PGD2 receptor antagonist. In detail, the present invention provides a composition for the prevention or treatment of itching caused by an antigen, especially a composition for the treatment of itching derived from atopic dermatitis, urticaria, allergic conjunctivitis, allergic rhinitis or contact dermatitis.
A PGD2 receptor antagonist used in the present invention has an activity of preventing or treating itching and so it is able to be used for a pharmaceutical composition for the prevention or treatment of itching. The term xe2x80x9citchingxe2x80x9d to be used in the present specification means itching caused by an allergic reaction or a non-allergic reaction.
The allergic reaction means reactions caused by the activation of mast cell, basophil and the like due to the reaction of an antigen with the antigen-specific IgE and the delayed-type allergy reaction such as contact dermatitis. The non-allergic reaction means a reaction which is independent of IgE and caused by mast cells, basophils and the like activated by a chemical substance or the like.
The PGD2 receptor antagonist suppresses itching derived from the allergic reaction or non-allergic reaction and is useful for the prevention or treatment of the accompanying inflammation such as atopic dermatitis, urticaria, allergic conjunctivitis, allergic rhinitis, contact dermatitis and the like.
Moreover, the PGD2 receptor antagonist is useful for the prevention or treatment of a secondary disease such as cararacta, retinal separation, inflammation, infection, dysgryphia or the like, which is caused by an action accompanied by itching, for example, scratching, knocking and the like.
The PGD2 receptor antagonist used in the present invention has an activity of preventing or treating itching. Among them, preferred is a composition for the prevention or treatment of itching comprising a compound of the following formula (I).
In a preferred embodiment, the PGD2 receptor antagonist includes a compound of the formula (I): 
R is hydrogen, alkyl, alkoxy, halogen, hydroxy, acyloxy or optionally substituted arylsulfonyloxy, X is hydrogen or alkyl and the double bond on the xcex1 chain has E configuration or Z configuration, a pharmaceutically acceptable salt thereof or a hydrate thereof.
Through the present specification, the group of the formula in the compound of the formula (I): 
wherein X is as defined above,
is referred to as xcex1 chain and the group of the formula: 
wherein R is as defined above,
is referred to as xcfx89 chain.
The double bond on the xcex1 chain has E configuration or Z configuration.
In detail, examples of the above compound include a compound of the formula (IA): 
wherein R and X are as defined above and the double bond on the xcex1 chain has E configuration or Z configuration, and a compound of the formula (IB): 
xe2x80x83wherein R and X are as defined above and the double bond on the xcex1 chain has E configuration or Z configuration.
In more detail, the compound of the formula (IA) includes a compound of the formula: 
wherein R and X are as defined above and the double bond on the xcex1 chain has E configuration or Z configuration.
Preferred is the compound of the formula (IA-a), (IA-b), (IA-c), (IA-d) or (IA-bxe2x80x2). Especially preferred is the compound of the formula (IA-a).
The compound of the formula (IB) includes a compound of the formula: 
wherein R and X are as defined above and the double bond on the xcex1 chain has E configuration or Z configuration.
Preferred is the compound of the formula (IB-axe2x80x2) or (IB-bxe2x80x2).
Among the above examples, preferred is a compound wherein the double bond on the xcex1 chain has E configuration, a compound wherein the double bond on the xcex1 chain has Z configuration, a compound wherein R is hydrogen, methyl, methoxy, bromo, fluoro, hydroxy, acetoxy or phenylsulfonyloxy and X is hydrogen or a compound wherein R is hydroxy and X is hydrogen.
Preferred is a compound of the formula (IA-a-5): 
A preferred PGD2 receptor antagonist has a high PGD2 antagonistic activity and a high selectivity. Another preferred has a low agonistic activity. For example, a preferred antagonist has a PGD2 binding inhibitory activity (IC50 value) of 1000 nM or less, 100 nM or less or especially 10 nM or less. The PGD2 binding inhibitory activity (IC50 value) can be calculated in accordance with the experiment 1 of the present specification.
Each term used in the present specification is defined below.
The term xe2x80x9calkylxe2x80x9d means C1-C6 straight or branched alkyl, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, neopentyl, t-pentyl, t-pentyl, hexyl and the like.
The term xe2x80x9calkoxyxe2x80x9d means C1-C6 straight or branched alkoxy, for example, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy and the like.
The term xe2x80x9chalogenxe2x80x9d is fluoro, chloro, bromo or iodo.
The term xe2x80x9cacylxe2x80x9d of the term xe2x80x9cacyloxyxe2x80x9d means C1-C9 acyl derived from aliphatic carboxylic acid, for example, formyl, acetyl, propionyl, butyryl, valeryl and the like.
The term xe2x80x9cacyloxyxe2x80x9d means acyloxy derived from the above xe2x80x9cacylxe2x80x9d, for example, acetoxy, propionyloxy, butyryloxy, valeryloxy and the like.
The term xe2x80x9carylxe2x80x9d means C6-C14 aromatic monocyclic group or aromatic condensed ring, for example, phenyl, naphthyl (e.g., 1-naphthyl or 2-naphthyl), anthryl (e.g., 1-anthryl, 2-anthryl or 9-anthryl) and the like.
The term xe2x80x9carylsulfonyloxyxe2x80x9d means arylsulfonyloxy derived from xe2x80x9carylxe2x80x9d, for example, arylsulfonyloxy, 1-nathylsulfonyloxy, 1-anthrylsulfonyloxy and the like. The substituent of xe2x80x9carylxe2x80x9d includes alkyl, alkoxy, halogen, hydroxy and the like.
Examples of salts of the compound of the formula (I) includes those formed with an alkali metal (e.g., lithium, sodium or potassium), an alkali earth metal (e.g., calcium), an organic base (e.g., tromethamine, trimethylamine, triethylamine, 2-aminobutane, t-butylamine, diisopropylethylamine, n-butylmethylamine, cyclohexylamine, dicyclohexylamine, N-isopropylcyclohexylamine, furfurylamine, benzylamine, methylbenzylamine, dibenzylamine, N,N-dimethylbenzylamine, 2-chlorobenzylamine, 4-methoxybenzylamine, 1-naphthalenemethylamine, diphenylbenzylamine, triphenylamine, 1-naphthylamine, 1-aminoanthracene, 2-aminoanthracene, dehydroabiethylamine, N-methylmorpholine or pyridine), an amino acid (e.g., lysine or arginine) and the like. These salts can be formed in accordance with the general method.
The hydrates of the compound of the formula (I) may be coordinated with water molecules in an optional proportion.
The compound of the formula (I) may have all the possible stereo configurations, that is, the double bond on the xcex1 chain has E configuration or Z configuration and the bond binding to the bicyclic ring is of R configuration or S configuration, including all the stereo isomers (diastereomers, epimers, enantiomers and the like), racemates and mixtures thereof.
General processes for the preparation of the compound of the formula (I) are illustrated as follows. Any substituent interfering with a reaction may be protected in advance with a protecting group and deprotected in a suitable step.
Process 1
wherein Y ring, X and R are as defined above and the double bond on the xcex1 chain has E configuration or Z configuration.
The compound of the formula (I) as shown in the above process 1 can be prepared by reacting the carboxylic acid of the formula (III) or the reactive derivative with an amino compound of the formula (II).
In this process, a starting compound (II) wherein 
is described in the Japanese Patent Publication (Kokoku) No. 23170/1994. A compound (II) wherein 
is described in the Japanese Patent Publication (Kokai) Nos. 49/1986 and 180862/1990.
The carboxylic acid of the formula (III) includes 4-bromobenzo[b]thiophene-3-carboxylic acid, 5-bromobenzo[b]thiophene-3-carboxylic acid, 6-bromobenzo[b]thiophene-3-carboxylic acid, 7-bromobenzo[b]thiophene-3-carboxylic acid, 5-fluorobenzo[b]thiophene-3-carboxylic acid, 6-fluorobenzo[b]thiophene-3-carboxylic acid, 4-hydroxybenzo[b]thiophene-3-carboxylic acid, 5-hydroxybenzo[b]thiophene-3-carboxylic acid, 6-hydroxybenzo[b]thiophene-3-carboxylic acid, 7-hydroxybenzo[b]thiophene-3-carboxylic acid, 5-acetoxybenzo[b]thiophene-3-carboxylic acid, benzo[b]thiophene-3-carboxylic acid, 5-benzosulfonyloxybenzo[b]thiophene-3-carboxylic acid, 5-methylbenzo[b]thiophene-3-carboxylic acid, 6-methylbenzo[b]thiophene-3-carboxylic acid, 5-methoxybenzo[b]thiophene-3-carboxylic acid and 6-methoxybenzo[b]thiophene-3-carboxylic acid. These carboxylic acids may have the substituents as defined above.
These carboxylic acids can be prepared in accordance with methods as described in Nippon Kagaku Zasshi Vo.l 88, No. 7, 758-763 (1967), Nippon Kagaku Zasshi Vol. 86, No. 10, 1067-1072 (1965), J. Chem. Soc (c) 1899-1905 (1967), J. Heterocycle. Chem. Vol. 10 679-681 (1973), J. Heterocyclic Chem. Vol 19 1131-1136 (1982) and J. Med. Chem. Vol. 29 1637-1643 (1986).
The reactive derivative of carboxylic acid of the formula (III) means the corresponding acid halide (e.g., chloride, bromide, iodide), acid anhydride (e.g., mixed acid anhydride with formic acid or acetic acid), active ester (e.g., succinimide ester) and the like, including acylating agents used for the acylation of amino group. For example, when an acid halide is employed, the compound (III) is reacted with a thionyl halide (e.g., thionyl chloride), phosphorous halide (e.g., phosphorous trichloride, phosphorous pentachloride), oxalyl halide (e.g., oxalyl chloride) and the like, in accordance with known methods as described in the literatures (e.g., Shin-Jikken-Kagaku-Koza, Vol. 14, 1787 (1978); Synthesis 852-854 (1986); Shin-Jikken-Kagaku-Koza Vol. 22, 115 (1992)).
The reaction of Process 1 can be conducted under a condition generally used for the acylation of amino group. For example, in a case of condensation with the acid halide, the reaction is carried out in a solvent such as an ether solvent (e.g., diethyl ether, tetrahydrofuran, dioxane), benzene solvent (e.g., benzene, toluene, xylene), halogenated hydrocarbon solvent (e.g., dichloromethane, dichloroethane, chloroform) as well as ethyl acetate, dimethylformamide, dimethyl sulfoxide and acetonitrile, if necessary, in the presence of a base (e.g. organic base such as triethylamine, pyridine, N,N-dimethylaminopyridine and N-methylmorpholine; inorganic base such as sodium hydroxide, potassium hydroxide and potassium carbonate. The reaction temperature is under cooling, at room temperature or under heating, preferably at a temperature ranging from xe2x88x9220xc2x0 C. to ice-cooling temperature or from room temperature to a refluxing temperature of the reaction system. The reaction time is several minutes to several ten hours, preferably 0.5 hr to 24 hr and particularly 1 hr to 12 hr. In a case of using the carboxylic acid in a free form without converting into the reactive derivative, the reaction is conducted in the presence of a condensing agent (e.g., dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-methylaminopropyl)carbodiimide, N,Nxe2x80x2-carbonyldiimidazole) usually used in the condensation reaction of amine with carboxylic acid.
The compound (I) of the present invention can be also prepared in accordance with a method as follows.
Process 2
wherein Y ring, R and X are as defined above and the double bond on the xcex1-chain has E configuration or Z configuration.
(Step 1)
In this step, the compound of the formula (V) can be prepared by reacting the amino compound of the formula (IV) with a carboxylic acid of the formula (III) or its reactive derivative, in accordance with Process 1. As to some of the amino compounds of the formula (IV), the process is disclosed in Chem. Pharm. Bull. Vol. 37, No. 6, 1524-1533 (1989).
(Step 2)
In this step, a compound of the formula (V) is oxidized to give an aldehyde compound of the formula (VI). This step may be carried out with chromated oxidizing agents such as Jones"" reagent, Collins"" reagent, pyridinium chlorochromate and pyridinium dichromate, in a solvent such as chlorinated hydrocarbon (e.g., chloroform, dichloromethane), ether (e.g., ethyl ether, tetrahydrofuran), acetone, benzene and the like, under cooling or at room temperature for several hours. This step may be also carried out with oxidizing agents in combination with appropriate activator agents (e.g., trifluoroacetic anhydride, oxalyl chloride) and dimethyl sulfoxide, if necessary, in the presence of base (e.g. organic base such as triethylamine, diethylamine).
(Step 3)
In this step, the xcex1 chain of an aldehyde compound of the formula (VI) is formed to give the compound of the formula (I). The compound of the formula (I) can be prepared by reacting the aldehyde compound of the formula (VI) with an ylide compound corresponding to the rest part of the xcex1 chain in accordance with conditions of the Wittig reaction. Further, the ylide compound corresponding to the rest part of the xcex1 chain can be synthesized by reacting triphenylphosphine with a corresponding halogenated alkanoic acid or ester derivative thereof in the presence of a base according to a well known method.
In a reaction of the other free acid or the reactive derivative with the amine (II) or (IV), depending on the property of each free acid or the reactive derivative, the reaction conditions are determined in accordance with a known method. The reaction product can be purified by a conventional method, such as extraction with a solvent, chromatography, recrystallization and the like.
The objective compound (I) in the present invention can be converted into a corresponding ester derivative, if desired. For example, the ester can be prepared by esterification of a carboxylic acid in accordance with a known method. If desired, E isomer, Z isomer or the mixture can be produced depending on the reaction conditions.
When using a PGD2 antagonist of the present invention for treatment, it can be formulated into ordinary formulations for oral and parenteral administration. A pharmaceutical composition containing a PGD2 antagonist of the present invention can be in the form for oral and parenteral administration. Specifically, the oral formulation includes tablets, capsules, granules, powders, syrup and the like. The parenteral formulation includes injectable solutions or suspensions for intravenous, intramuscular or subcutaneous injection, inhalants, eye drops, nasal drops, suppositories or percutaneous formulations such as ointment, patches and poultices. Preferred is an oral or percutaneous formulation.
In preparing the formulations, carriers, excipients, solvents and bases known to presons ordinary skilled in the art may be used. Tablets are prepared by compressing or fomulating an active ingredient together with auxiliary components. Examples of the auxiliary components include pharmaceutically acceptable excipients such as binders (e.g., cornstarch), fillers (e.g., lactose, microcrystalline cellulose), disintegrants (e.g., starch sodium glycolate) and lubricants (e.g., magnesium stearate). Tablets may be coated appropriately. In the case of liquid formulations such as syrups, solutions or suspensions, they may contain suspending agents (e.g., methyl cellulose), emulsifiers (e.g., lecithin), preservatives and the like. Injectable formulations may be in the form of solution or suspension or oily or aqueous emulsion, which may contain a suspension-stabilizing agent or dispensing agent and the like. Percutaneous formulations such as ointment, patches, poultices and the like may be prepared by using water base (e.g., water, lower alcohol, polyol) or oil base (higher fatty acid ester (isopropyl myristate), lipophilic alochol).
An appropriate dosage of PGD2 receptor antagonist, depending on the administration route, age, body weight, sex or conditions of the patient and the kind of optionally combined drug(s), should be determined by a physician. In the case of oral administration, the daily dosage can generally be between about 0.01-100 mg, preferably about 0.01-10 mg, more preferably about 0.01-1 mg, per kg body weight. In the case of parenteral administration, the daily dosage can generally be between about 0.001-100 mg, preferably about 0.001-1 mg, more preferably about 0.001-0. 1 mg, per kg body weight. The daily dosage can be administered in 1-4 divisions.
The following Examples are provided to further illustrate the present invention and are not to be construed as limiting the scope.
The abbreviations used throughout the examples are shown as follows.
Me methyl
Ac acetyl
Ph phenyl

To a solution of 8.63 g (44.4 mmol) of 5-hydroxybenzo[b]thiophene-3-carboxylic acid (1) (J. Chem. Soc (C), 1899-1905 (1967), M. Martin-Smith et al.) in 160 ml of 80% aqueous tetrahydrofuran and 44 ml of 1N sodium hydroxide were added dropwised 87 ml of 0.56N sodium hydroxide and 6.2 ml (48.4 mmol) of benzenesulfonylchloride simultaneously with keeping at pH 11-12 and stirring under ice-cooling. After the reaction, the mixture was diluted with water, alkalized and washed with toluene. The aqueous layer was weakly acidified with conc. hydrochloric acid under stirring. The precipitated crystals were filtered, washed with water and dried to give 14.33 g of 5-benzenesulfonyloxybenzo[b]thiophene-3-carboxylic acid (2).
mp 202-203xc2x0 C.
NMR xcex4 (CDCl3), 300 MHz
7.16 (1H, dd, J=2.7 and 9.0 Hz), 7.55-7.61 (2H, m), 7.73 (1H, m), 7.81 (1H, d, J=9.0 Hz), 7.90-7.94 (2H, m), 8.16 (1H, d, J=2.7 Hz), 8.60 (1H, s).
IR(Nujol): 3102, 2925, 2854, 2744, 2640, 2577, 1672, 1599, 1558, 1500, 1460, 1451 cmxe2x88x921 
Elemental analysis (for C15H10O5S2). Calcd. (%): C, 53.88; H, 3.01; S, 19.18. Found (%): C, 53.83; H, 3.03; S, 19.04.
A mixture of 5.582 g (16.7 mmol) of the above obtained 5-benzenesulfonyloxybenzo[b]thiophene-3-carboxylic acid (2), a drop of dimethylformamide, 3.57 ml (50 mmol) of thionyl chloride and 22 ml of toluene was refluxed for 1.5 hours and then concentrated under reduced pressure to give 5.89 g of the objective compound (3).

A solution of 100 mg (0.3 mmol) of the above obtained 5-benzenesulfonyloxybenzo[b]thiophene-3-carboxylic acid (2) in 1.2 ml of 1N sodium hydroxide was stirred at 40xc2x0 C. for 8 hours. Hydrochloric acid (1N, 1.2 ml) was added thereto and the precipitated crystals were filtered, washed with water and dried to give 58 mg of 5-hydroxybenzo[b]thiophene-3-carboxylic acid (1). Yield 96.6%.
mp 262-263xc2x0 C.
A solution of 1,140 mg of the above obtained 5-hydroxybenzo[b]thiophene-3-carboxylic acid (1) in 2 ml of acetic anhydride and 4 ml of pyridine was allowed to stand for 3 hours. After addition of water, the mixture was stirred for 1.5 hours under ice-cooling and the precipitated crystals were filtered, washed with water and dried to give 1,349 mg of 5-acetoxybenzo[b]thiophene-3-carboxylic acid (4). Yield 97.3%.
mp 239-240xc2x0 C.
A mixture of 1,349 mg of the above obtained 5-acetoxybenzo[b]thiophene-3-carboxylic acid (4), a drop of dimethylformamide, 1.22 ml of (17.13 mmol) of thionyl chloride and 25 ml of toluene was refluxed for 1.5 hours and then concentrated under reduced pressure to give 1,454 mg of the objective compound (5).

The compound (6) (Chem. Pharm. Bull. Vol. 37, No. 6 1524-1533 (1989)) was reduced with sodium according to the method described in the above literature and the compound (IVA-a-1) was removed by filtration as the benzoic acid salt. The mother liquor (79 g) was suspended in 150 ml of ethyl acetate, adding 260 ml of 1N-hydrochloric acid and the mixture was stirred. The separated aqueous layer was basified with 65 ml of 4N-sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Of the obtained oily residue (30 g), 6.7 g was dissolved in 40 ml of 90% methanol, adsorbed to 500 ml of an ion-exchange resin, Amberlite CG-50 (NH4+)type I and eluted with 2.2 L of water and 1N 2.2 L of aqueous ammonia by a gradient method.
One fraction: 300 ml. Each fraction was checked by thin-layer chromatography (the developing solvent; chloroform:methanol:conc. aqueous ammonia=90:10:1). The fractions 3-8 were collected and concentrated under reduced pressure. The residue was crystallized from hexane; recrystallization afforded 538 mg of needles.
mp 117-118xc2x0 C.
NMR xcex4 (CDCl3), 300 MHz
1.01 and 1.21 (each 3H, each s), 1.34 (1H, d, J=9.9 Hz), 1.52-1.66 (2H, m),
1.90-2.07 (4H, m), 2.18 (1H, m), 2.48 (1H, m), 3.12 (3H, bs), 3.49 (1H, dd, J=3.9 and 9.6 Hz), 3.61 (1H, dt, J=2.4 and 10.5 Hz), 3.84 (1H, ddd, J=3.3, 4.8 and 10.5 Hz).
IR(Nujol): 3391, 3293, 3108, 2989, 2923, 2869, 2784, 2722, 2521, 1601, 1489, 1466 cmxe2x88x921 
[xcex1]D23xe2x88x922.5xc2x0 (c=1.02, CH3OH)
Elemental analysis for (C11H21NO). Calcd.: (%): C, 72.08; H, 11.55; N, 7.64. Found: (%): C, 72.04; H, 11.58; N, 7.58.
By means of X-ray crystal analysis, the obtained compound was identified as (1R, 2R, 3S, 5S)-2-(2-amino-6,6-dimethylbicyclo[3.1.1]hept-3-yl)ethanol (IVA-c-1). The mother liquor (2.9 g) after the recrystallization from hexane was dissolved in 15 ml of ethyl acetate, to which was added a solution of 30 ml of ethyl acetate containing 1.93 g of benzoic acid. The precipitated crystals were filtered to give 2.93 g of the benzoic acid salt of the compound (IVA-a-1).
mp 182-183xc2x0 C.
The fractions 10-17 were collected and concentrated under reduced pressure. To a solution of 2.66 g of the residue in 15 ml of ethyl acetate was added 11 ml of ethyl acetate containing 1.77 g of benzoic acid. The precipitated crystals were filtered to give 4.08 g of needles.
mp 160-161xc2x0 C.
NMR xcex4 (CDCl3), 300 MHz 0.61 and 1.06 (each 3H, each s), 1.36 (1H, m), 1.53-1.65 (2H, m), 1.75-1.88 (2H, m), 1.95-2.04 (4H, m), 3.18 (1H, d, J=6.3 Hz), 3.58 (1H, dt, J=3.0 and 10.8 Hz), 3.81 (1H, m), 5.65 (4H, bs), 7.33-7.42 (3H, m), 7.98-8.01 (2H, m).
IR(Nujol): 3320, 2922, 2854, 2140, 1628, 1589, 1739, 1459, 1389 cmxe2x88x921 
[xcex1]D23xe2x88x9231.8xc2x0 (c=1.01, CH3OH)
Elemental analysis (for C18H27NO3). Calcd.: (%): C, 70.79; H, 8.91; N, 4.59. Found: (%): C, 70.63; H, 8.86; N, 4.58.
By means of X-ray crystal analysis, the structural formula was identified as that of (1R, 2S, 3S, 5S)-2-(2-amino-6,6-dimethylbicyclo[3.1.1]hept-3-yl)ethanol (IVA-b-1).